Funded RDCC Pilot and Feasibility Study #1 Title: Role of ISG15 in the pathogenesis of SLE PI: Deborah J. Lenschow, M.D., Ph.D. A. Specific Aims: Systemic lupus erythematosis (SLE) is a chronic autoimmune disease characterized by the loss of tolerance to nuclear antigens and the development of pathogenic autoantibodies, resulting in injury to multiple organ systems. Recent studies have implicated type I interferons (IFNs) in the pathogenesis of SLE;however, the downstream IFN effector molecules that mediate these actions are poorly understood. We proposed the following aims to evaluate the role of a recently identified and characterized IFN induced molecule, ISG15, in the pathogenesis of SLE. Aim 1. Determine if ISG15 functions as a cytokine to regulate immune responses. Aim 2. Determine if ISG15 plays a role in the pathogenesis of SLE. During the course of these studies it became apparent that while IFNs are known to play a role in the pathogenesis of SLE in various murine models, little is known about the cell type specific effects of this class of cytokines in these models. We have obtained or are developing reagents for other projects in the lab that will allow us to evaluate cell type specific effects of type I IFNs. We propose to utilize these reagents to pursue this question in murine models of SLE. Aim 3. Determine the cell type specific effects of Type I IFNs in the pathogenesis of SLE.